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Graham Warwick

Publications and source records attributed to Graham Warwick.

4 recordsLinked to original sources
PubMed2006

The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD.

BACKGROUND: Evaluating the effects of decreasing low-density lipoprotein (LDL) cholesterol levels requires large randomized trials. In preparation for such a trial, we assessed the biochemical efficacy, safety, and tolerability of adding ezetimibe, 10 mg/d, to simvastatin, 20 mg/d, as initial therapy for such patients. METHODS: Two hundred three patients (152 predialysis patients with creatinine levels > or = 1.7 mg/dL [> or = 150 micromol/L], 18 patients on peritoneal dialysis therapy, and 33 patients on hemodialysis therapy) were randomly assigned to the administration of simvastatin, 20 mg/d, plus ezetimibe, 10 mg/d; or simvastatin, 20 mg, plus placebo ezetimibe daily. RESULTS: After 6 months, allocation to simvastatin monotherapy was associated with a 31-mg/dL (0.8-mmol/L) decrease in nonfasting LDL cholesterol levels compared with baseline. Allocation to simvastatin plus ezetimibe produced an additional 18-mg/dL (0.47-mmol/L) decrease in LDL cholesterol level, representing an incremental 21% reduction over that achieved with simvastatin monotherapy (P < 0.0001). There were no statistically significant effects of the addition of ezetimibe to simvastatin on triglyceride or high-density lipoprotein cholesterol levels. Ezetimibe was not associated with an excess risk of abnormal liver function test results or of elevated creatine kinase levels and did not impair absorption of fat-soluble vitamins. There were no serious adverse events caused by study treatment. CONCLUSION: This 6-month study shows that the addition of ezetimibe to simvastatin, 20 mg/d, as initial therapy for patients with chronic kidney disease was well tolerated and produced an additional 21% decrease in LDL cholesterol levels. The clinical efficacy and safety of combination therapy in this population are now being assessed in a large randomized trial.

Anticholesteremic Agents↗
PubMed2005

Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome.

Mutations in the plasma complement regulator factor H (CFH) and the transmembrane complement regulator membrane co-factor protein (MCP) have been shown to predispose to atypical hemolytic uremic syndrome (HUS). Both of these proteins act as co-factors for complement factor I (IF). IF is a highly specific serine protease that cleaves the alpha-chains of C3b and C4b and thus downregulates activation of both the classical and the alternative complement pathways. This study looked for IF mutations in a panel of 76 patients with HUS. Mutations were detected in two patients, both of whom had reduced serum IF levels. A heterozygous bp change, c.463 G>A, which results in a premature stop codon (W127X), was found in one, and in the other, a heterozygous single base pair deletion in exon 7 (del 922C) was detected. Both patients had a history of recurrent HUS after transplantation. This is in accordance with the high rate of recurrence in patients with CFH mutations. Patients who are reported to have mutations in MCP, by contrast, do not have recurrence after transplantation. As with CFH- and MCP-associated HUS, there was incomplete penetrance in the family of one of the affected individuals. This study provides further evidence that atypical HUS is a disease of complement dysregulation.

Adult↗
PubMed2005

First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular disease, but the efficacy and safety of simvastatin and aspirin are unknown in this patient group. METHODS: Patients were randomly assigned in a 2 x 2 factorial design to the administration of: (1) 20 mg of simvastatin daily versus matching placebo, and (2) 100 mg of modified-release aspirin daily versus matching placebo. RESULTS: Overall, 448 patients with chronic kidney disease were randomly assigned (242 predialysis patients with a creatinine level > or = 1.7 mg/dL [> or =150 micromol/L], 73 patients on dialysis therapy, and 133 patients with a functioning transplant). Compliance with study treatments was 80% at 12 months. Allocation to treatment with 100 mg of aspirin daily was not associated with an excess of major bleeds (aspirin, 4 of 225 patients [2%] versus placebo, 6 of 223 patients [3%]; P = not significant [NS]), although there was a 3-fold excess of minor bleeds (34 of 225 [15%] versus 12 of 223 patients [5%]; P = 0.001). Among those with predialysis renal failure or a functioning transplant at baseline, aspirin did not increase the number of patients who progressed to dialysis therapy (7 of 187 [4%] versus 6 of 188 patients [3%]; P = NS) or experienced a greater than 20% increase in creatinine level (63 of 187 patients [34%] versus 56 of 188 patients [30%]; P = NS). After 12 months of follow-up, allocation to 20 mg of simvastatin daily reduced nonfasting total cholesterol levels by 18% (simvastatin, 163 mg/dL [4.22 mmol/L] versus placebo, 196 mg/dL [5.08 mmol/L]; P < 0.0001), directly measured low-density lipoprotein cholesterol levels by 24% (89 mg/dL [2.31 mmol/L] versus 114 mg/dL [2.96 mmol/L]; P < 0.0001), and triglyceride levels by 13% (166 mg/dL [1.87 mmol/L] versus 186 mg/dL [2.10 mmol/L]; P < 0.01), but there was no significant effect on high-density lipoprotein cholesterol levels (2% increase; P = NS). Allocation to simvastatin therapy was not associated with excess risk for abnormal liver function test results or elevated creatine kinase levels. CONCLUSION: During a 1-year treatment period, simvastatin, 20 mg/d, produced a sustained reduction of approximately one quarter in low-density lipoprotein cholesterol levels, with no evidence of toxicity, and aspirin, 100 mg/d, did not substantially increase the risk for a major bleeding episode. Much larger trials are now needed to assess whether these treatments can prevent vascular events.

Adult↗